Sudden cardiac death (SCD) has been referred to as the most challenging problem facing contemporary cardiology. Most sudden deaths are unexpected, unheralded by symptoms of any duration or by overt coronary artery disease (CAD). It is thought that the mechanism responsible for the great majority of SCD is ventricular fibrillation (VF), a state in which the normally organized electrical activity of the heart becomes disorganized. This disorganized electrical activity initiates similarly disorganized and ineffectual mechanical contractions of the pumping chambers of the heart, resulting in circulatory collapse and death.
By far the most desirable and potentially the most effective response to the problem of SCD is prevention, in which the first step would be the identification of those individuals at increased risk. It is this identification with which the present invention is concerned.
Once identified, there are several methods to treat such patients. A first method is antiarrhythmic drugs. A second method is implantable defibrillators. A third method is cardiac ablation. Because of the side effects of drugs and the surgical risks involved with the implantable defibrillator and ablation treatments, a patient is examined carefully before receiving a therapy. The patient's propensity for VF is determined by attempting to induce such irregular cardiac behavior through invasive electrophysiological studies. These studies provide the basis for deciding the best treatment for a patient, but the studies themselves involve a significant likelihood of pain and risk of death. There is a need for a noninvasive and safe means of determining which patients are at increased risk for SCD.
The standard method for a noninvasive and safe means to determine a patient's risk of SCD is the time-domain signal averaged electrocardiography (ECG) method and apparatus with the ECG electrodes positioned in the Frank orthogonal configuration. The time-domain signal averaged ECG or its frequency-domain embodiments have been in use for 15 years, and much work has been done to understand its capabilities and limitations. Unfortunately, there are many questions that remain unanswered about the ability of the signal averaged ECG to accurately assess a patient for increased risk of SCD. As recently as June 1994, Hnatkova and colleagues found that different filters and filter settings produce discordant results of the signal averaged ECG when using the same instrument, complicating the well-known fact that the use of different recording systems produces conflicting results (PACE 1994; 17: 1107-1117). Hence, this particular set of prior art methods and devices has been unable to adequately identify, patients with an increased risk of SCD. Attempts to use signal averaged ECG therefore have met with limited success.
U.S. Pat. No. 4,802,491 to Cohen and Smith discloses a passive method of detecting subtle alternations in the morphologic features of the ECG, called alternans, to determine a patient's increased risk of SCD. In a study published in the New England Journal of Medicine (1994; 330: 235-241) on a small set of patients, Cohen et at. discovered that their method provided a capability equal to that of the signal averaged ECG; in particular, T-wave alternans ratios were greater in patients with inducible arrhythmias when compare to those patients that could not be induced. Unfortunately, their method required the transvenous insertion of a recording-stimulating catheter into a patient's heart, and their apparatus then paced the patient's heart at 100 beats per minute. As discussed in their publication, their method and apparatus were limited by the invasive procedure, and improvements in their method were needed to compensate for fluctuations in heart rate associated with normal sinus rhythm. Additionally, they acknowledged that there are limitations regarding the sensitivity and reliability of their technique. These limitations are derived from the need to distinguish alternans-type fluctuations in the ECG from larger fluctuations due to noise or other physiologic fluctuations such as respiration. Additionally, the Cohen et al. method and apparatus provide a correlational relation between T-wave alternans and the results of electrophysiological testing. No information is provided regarding the actual, anatomical and dynamical state of the heart. Therefore, this prior art device has been unable to provide a noninvasive, safe, and highly accurate means to identify patients with an increased risk of SCD.
To this point then it had not been possible to accurately identify patients with increased risk of SCD in a safe and noninvasive manner. Despite the need for such a method and apparatus, there is only one apparatus, insofar as is known, that is capable of identifying patients with increased risk of SCD safely and noninvasively. The apparatus disclosed in U.S. Pat. Nos. 5,117,834 and 5,351,687 to Kroll et al. (hereinafter called the "Kroll patents") determines the risk of SCD by "microinduction." There are significant limitations to this apparatus.
The Kroll patents disclose that an active, far-field application of current across the heart will change the way diseased cells depolarize, that these changes are seen by surface ECG, and that the method and apparatus can discern these activation changes by computing a specially designed sum of differences between a plurality of current-injected cardiac cycles and undisturbed cardiac cycles. Although the electrocardiographic changes created and measured by the disclosed apparatus are valid, how and why compromised or depressed myocardial substrates provide an electrophysiological dynamic to support the changes incurred by this active facilitation (AF) is subject to criticism.
With a careful review of the published theoretical and clinical research, we ascertain a more complete and appropriate understanding regarding the electrophysiological process of AF that permits us to determine and develop significant improvements over the teachings of the prior art.
We begin by considering the myocardial tissue of the heart. An electrical wave front is propagated across the tissue by the local circuit activity from one cardiac cell to the next through interconnective tissue. The local circuit current in the heart is produced by an intracellular potential gradient and is responsible for the propagation of electrical impulses in excitable tissue. For each cell, the current diffuses electrotonically across the intracellular substrate, is forced outward across the cell membrane by a resulting transmembrane potential, and flows back towards the source through the extracellular space. Due to the resistive nature of the tissue, the resulting membrane depolarization is largest near the source, where the cell is connected to other depolarizing cells, and decreases monotonically with distance. The area of excitable cellular membrane closest to the source is depolarized and generates inward ionic current. Propagation across the cell is attained when the amount of inward current exceeds that amount of the outward current found over the remainder of the membrane. In addition, because overall conduction depends on these local current circuits, the speed at which an electrical wave front is propagated across myocardial tissue is determined by the coupling resistance between cells, such that the propagation velocity decreases with increasing coupling resistance.
Possible causes for propagation failure across a section of tissue can be due to reduced intracellular potential, lowered excitability, or regions of increased tissue resistivity. For example, progressive interstitial fibrosis during aging in myocardial tissues results in a loss of electrical coupling. As another example, disruption of side-to-side connections in ischemic or infarcted tissues increase path lengths and the number of intercellular junctions traversed by an electrical wave front moving in transverse directions. Further, the loss of orientation of the tissue increases the complexity of the tissue and increases activation delay. All of these problems can and do occur in tissue that has been compromised by various heart diseases, such as CAD and its complications of myocardial infarction, acute and chronic ischemia, and congestive heart failure.
These problems are well understood, and are described in the published literature, both at a cellular level and at a tissue level. One of the earliest references was by Boineau and Cox in Circulation (1973; 48: 702-713), in which they described the desynchronization and marked slowing of previously uniform activation that occurs across infarcted and ischemic tissue. The observed electrical activity resembled abbreviated, local fibrillation. These effects are now called "fractionation." One of the most recent studies was published by de Bakker et al. in Circulation (1993; 88: 915-926), demonstrating a "zigzag" course of activation at high speeds. The activation wave front proceeds along circuitous routes lengthened by branching and merging bundles of myocardial tissues that have survived infarction or ischemia.
Regarding these general issues of how electrical wave fronts are conducted across compromised myocardial tissues, Antzelevitch and Moe, in Circulation Research (1981; 49: 1129-1139) and the American Journal of Physiology (1983; 245: H42-H53), have recently clarified the underlying process of certain types of transmissions by showing that very slow conduction through ischemic areas can result from step delays imposed by electrotonic transmission of impulses across inexcitable or compromised segments of cardiac tissue rather than from uniform slow conduction of propagated action potentials. These subthreshold, electrotonic effects are called Wedensky facilitation or inhibition. In their experiments, they compared the characteristics of impulse conduction across an ischemic gap between two pieces of viable tissue. They showed that transmission across the gap was mediated by electrotonic displacement of membrane potential by subthreshold current pulses of appropriate duration passed through the ischemic gap. The activity recorded from the center of the gap segment was shown to comprise two components when impulse transmission across the ischemic gap was successful. The two components proved to be electrotonic images of the cellular responses at each end of the gap, thereby ruling out the possibility of active participation of the slow inward currents described earlier. Their experimental results suggested that electrotonic delay rather than slow response was responsible for slow conduction observed in depressed or compromised tissue. Antzelevitch et al. also showed that the subthreshold potentials recorded intracellularly from inexcitable zones, referred to as electrotonic potentials, were in fact local depolarizations (or hyperpolarizations), which depended on several variables, including the amount of the inexcitable tissue, tissue resistances, the amplitude of the wave front entering the tissue, and the excitability of the tissue beyond the problem area.
More importantly, their results further showed that the amplitude of an electrotonic potential emerging from the far end of inexcitable tissue must be large enough to bring excitable tissue to threshold if transmission was to succeed, and that the amplitude of the electrotonic potentials varied across the inexcitable tissue with respect to the levels of voltage that were encountered. In an important series of their experiments, they studied the effects of subthreshold depolarizing and hyperpolarizing current pulses on the amplitude of the electrotonic potential. They concluded that subthreshold pulses altered the threshold requirements for subsequent activation at the far end of the inexcitable gap by these traversing electrotonic potentials. They also determined that significant voltage and time dependencies of a facilitating or inhibitory nature existed, such that voltage-dependent effects varied with respect to the timing of delivered pulses.
The results of Antzelevitch et al. therefore provide substantial verification to several conclusions regarding the operational aspects of the present invention. First, Antzelevitch et al. provide significant results regarding the electrophysiological process and the possible effects of an external current pulse placed through the heart. They demonstrated that it is electrotonic delay rather than slow response that is responsible for slow conduction across depressed or inexcitable portions of the myocardium. Therefore, a process of external AF does not cause cells near threshold to necessarily depolarize or hyperpolarize but, rather, the AF enhances (by facilitating) or represses (by inhibiting) the naturally occurring electrotonic propagation of an electrical wave front across a section of compromised myocardial tissue. Therefore, we understand that a external current pulse delivered through the heart will indeed facilitate or inhibit electrical activity across such myocardial tissues, that the facilitation or inhibition from these pulses will indeed incur changes in a cardiac cycle, and that these changes can thereby be discovered with a careful and appropriate analysis of high-fidelity, high-resolution ECG signals taken from a patient's body.
Regarding how and why an external current pulse provides an electrical dynamic to support the changes incurred by active facilitation, far-field facilitation, as embodied by an external current pulse, must occur close to specific times during the cardiac cycle in which the diseased portion of the heart must function. These specific times are directly related to the compromised tissue's ability to allow the effective transfer of current across the tissue itself. Far-field facilitation has diminishing effects the further away in time that it occurs with respect to the conductive performance of the diseased portion of the heart. These specific points are supported by the results of Antzelevitch et al. suggesting that an external current pulse, delivered at the right moment in time, serves to change the membrane potential to allow less constrained, subthreshold depolarization across ischemic or infarcted tissues. The timing of a pulse is therefore critical, as further supported by the frequency-dependent, rate results. Further, delay across depressed tissue depends on the amount of this tissue, so that the size of the depressed tissue may be estimated by a subtle evaluation of the beat-to-beat changes produced by active facilitation.
The Kroll patents clearly show a manually operated, "hit or miss" aspect to a diagnostic strategy, with no effective means to determine how the more subtle aspects of AF can be used to further guide and refine the process of discovering diagnostic levels of myocardial electrical instability. The preferred embodiment of the apparatus shown therein teaches testing of a patient with a large combination of delivered facilitating pulses, in a manner designed to exhaustively search through a list of pulsing parameters and their ranges (such as delivery or sensing electrodes, current levels, pulse durations, and polarity). This diagnostic strategy is a significantly inefficient and possibly ineffective search for changes due to AF. The preferred embodiment of the apparatus further places an undue burden upon the physician to manually discern these subtle effects and to manually combine a large amount of data generated by such an exhaustively long sequence of facilitating pulses in order to guide the diagnostic activity. It is therefore not clear whether the physician can effectively manipulate the delivery of current pulses to implement a successful diagnostic searching strategy. For example, it can be seen to be, at the very least, a time consuming process to pinpoint the best time to deliver a facilitating pulse during a cardiac cycle. The physician is therefore left with relatively coarse results determined by a brute-force process of applying these pulses.
In a short paragraph referred to as an alternative embodiment, the Kroll patents propose a capability of varying the location of facilitating pulses until a maximal response is found, and then fixing the facilitating pulse to this timing location. It is dear from the teachings and implementation of the Kroll patents, however, that the positioning of the facilitating pulse to such a maximally responsive location is a manual and haphazard process by design, and does not in any way anticipate the present invention and its preferred embodiment as a significantly effective means to automate the diagnostic process of determining a level of myocardial electrical instability and thereby diagnosing a patient's risk for SCD.
The invention provides a method and apparatus to automatically and adaptively search for and discover the level of electrical instability of the heart by pulsing across a plurality of cardiac cycles in a way to optimally capture the electrophysiological information that indicates the possible location and amount of each diseased part. To this end, we describe a method and apparatus that are capable of diagnosing patients for increased levels of risk of SCD by using AF, externally and electrically probing the heart to provide an anatomical and electrophysiological assessment of a patient's damaged myocardium. We specifically propose to automate the process of AF (as defined by monitoring and evaluating outcomes from applying a sequence of current pulses to the heart) by defining and controlling a next AF step of this process according to the type of electrical response elicited from the myocardium due to a prior AF step. To realize this conceptual picture, we propose to use a nonlinear optimization method, called the simplex method, to iteratively evaluate a special "objective function" with inputs taken from a special "parameter-outcome" space. The simplex method and its searching strategy is therefore used to determine the next sequence of current pulses and their corresponding delivery across the heart according to the electrical activity measured from the delivery of a prior sequence of pulses.
The simplex method tracks optimum operating conditions for a process by evaluating an outcome from the process at a set of parameter points, or vertices, which form a simplex on a hypersurface defined in a parameter-outcome space, and continually forms new simplices by reflecting one point of a simplex in a hyperplane of the remaining points of the simplex. The simplex method adapts the simplex to the local landscape of the parameter-outcome space, elongating down long, inclined planes, changing direction on encountering curves on the surfaces in the space, and contracting in the neighborhood of the objective function's maximum (or minimum, depending on the purpose of the function). The simplex method operates to determine a global maximum value of the objective function as quickly as possible.
In the preferred embodiment of the invention, we construct a parameter-outcome space in which each parameter point or vertex, called an AF parameter point, defines a unique application of active facilitation to a patient's heart, specified by a set of numbers that describes a sequence of current pulses together with a set of corresponding pulse delivery and ECG monitoring instructions. Each parameter point therefore represents a set of instructions explaining how and when to deliver different types of pulses across a plurality of cardiac cycles and how and when to monitor and collect a plurality of ECG signals during this span of cardiac cycles. We use an objective function to facilitate electrical instability as the means to find and compare the subtle differences that may exist among the ECG signals collected during the active facilitation defined by a parameter point.
When an AF parameter point is input to the objective function, the objection function operates the present apparatus to implement AF defined by the parameter point, and computes a value, called the outcome, that represents the amount of difference as measured from the corresponding ECG signals collected during the AF. The simplex method, by the very definition of its searching strategy, actively and automatically selects new AF parameter points to input to the objective function. As described above, these AF parameter points are vertices in a simplex that is continually adapted to a surface in the parameter-outcome space, which, indeed, is a surface defined by the outcomes of the objective function. The simplex method searches for and discovers the largest outcome possible by evaluating a continual series of these "AF parameter vertices" with the objective function, using its searching strategy to guarantee that it will find the largest outcome and that it will find this largest outcome in an efficient and effective manner. We define an outcome of the objective function to represent a measure of the electrical instability of a patient's myocardium as elicited by AF. Utilizing the simplex method, the larger an outcome the more likely a patient has a high degree of myocardial electrical instability and thereby the more likely a patient may suffer from SCD.
We use the simplex method as the central element of a control program that automatically evaluates a patient safely and noninvasively to assess a patient's level of myocardial electrical instability. The simplex method, as the central element of the invention's control program, chooses a new sequence of facilitating pulses by predicting the effects that this facilitating sequence will have on the patient's heart. As will become apparent from the description of the invention in the preferred embodiment, the simplex method and the control program that operates this method most specifically overcome the significant limitations of the prior art.
The most effective and efficient way to implement the simplex method is to create an arbitrary, though constrained, sequence of facilitating pulses to "search" the electrical activity in a patient's myocardium. The invention therefore delivers an arbitrary sequence of pulses across the myocardium. Specifically, the invention delivers a plurality of pulses during a cardiac cycle. The invention further delivers any type or shape of current pulse during a cardiac cycle. The invention further acquires a plurality of high-fidelity ECG signals throughout a cardiac cycle whenever the ECG hardware is not blanked during the delivery period of a pulse.
Kavanagh et al. (PACE 1990; 13: 1268-1276) augment the clinical work of Antzelevitch et al. by demonstrating that certain types of fields, in the form of pulses, are more effective at incurring threshold or subthreshold action potentials than other types. For example, they showed that it was harder to stimulate a myocardial cell when its action potential at rest was higher than it would be under normal conditions. Normal myocardial cells have a resting transmembrane potential of approximately -90 mV. In the single cell model of the experiment, the application of a short depolarizing stimulation alone failed to evoke a response from a group of cells held at a resting transmembrane potential of -55 mV. In contrast, while first holding the resting transmembrane potential at -60 mV and then applying a hyperpolarizing pulse to transiently clamp the cells toward a more negative resting potential of -75 to -85 mV, the same depolarizing pulse was able to evoke an action potential, and was able to do so with a substantially shorter pulse. In addition, the hyperpolarizing pulse increased the upstroke velocity and amplitude of the evoked action potential as compared to those occurring with a depolarizing pulse alone. FIGS. 6 and 7 of the Kavanagh publication is particularly instructive regarding the effects of a depolarizing or hyperpolarizing pulse on cells with different values of resting transmembrane potential. The invention delivers a facilitating pulse from any pair of electrodes and with either polarity (positive or negative). The invention further combines two or more pulses to provide a single, shaped, polyphasic pulse.
Recent experiments have studied the effects of external, subthreshold fields, as short pubes, on the exaltability of a cardiac cell. The experimental results describing the electrical exaltability of a cardiac cell during exposure to an external field demonstrate that a cardiac cell anticipates the arrival of a far-field current pulse such that a pulse can reduce a cell's threshold for stimulation as much as 5 milliseconds before the pulse arrives, and the far-field effects due to a pulse across the cell membrane dissipate quickly after a generating source is removed and a pulse is no longer applied. The invention delivers a pulse at any specific time during a cardiac cycle. The invention delivers a pulse as short as 5 .mu.s in length and requiring a blanking period less than 50 .mu.s.
As a supporting counterpart to the clinical research work described above, many membrane models and computer simulations of action potential stimulation and action potential propagation in ventricular myocardium, based on clinical research data, have been proposed over the last fifty years. Specific to our purposes regarding AF and the invention, two recently published papers contain a significant set of results that further guide the implementation and operation of the invention. In the first paper, Leon and Roberge (IEEE Transactions on Biomedical Engineering 1993; 40: 1307-1319) model extracellular stimulation of cardiac cells. Leon and Roberge demonstrated that an effective stimulation of myocytes must take into account the shape of the pulse stimulus and its application in the cardiac cycle. They demonstrated that, because the intracellular space of a cell is very small, the cell's potential is nearly uniform over the length of the cell and the transmembrane potential is governed by the applied field. They further demonstrated that a cathodal (or negative) pulse is a preferred stimulus at diastole, that an anodal (or positive) pulse is a preferred stimulus during the plateau phase of the action potential, and that a biphasic pulse is best during the relative refractory period. The invention delivers biphasic (specifically polyphasic) facilitating pulses.
In a second paper, Pollard, Burgess and Spitzer (Circulation Research 1993; 72: 744-756) provided theoretical work with respect to the electrical activity of the heart as a whole. They used computer models which feature histological aspects of the heart to answer questions about how the shaping of the heart muscle can affect the timing and pattern of activation. They showed that portions of activation wave fronts that are aligned with myocardial fibers conduct faster than those wave fronts aligned across fibers, so that fiber rotation of a cardiac cell and inhomogeneous conductivity causes acceleration and deceleration of the spread of the activation wave front across the heart, thereby matching results observed and reported in epicardial activation maps from experimental animal studies. They therefore showed that electrical activity and wave front propagation in myocardium is nonuniformly anisotropic. AF may therefore provide an improved diagnostic ability if it were implemented in an optimal direction through the patient's torso and heart with respect to fiber rotation and orientation of the depressed or compromised tissue. The invention constructs, delivers, and evaluates an arbitrary sequence of facilitating pulses from a plurality of electrode pairs. The invention further provides an optimal means to evaluate the effects of any shaped pulse that is delivered at any time during a cardiac cycle across any specific section of the heart.
Another limitation of the prior art is the lack of teachings regarding the well-known problems that are created by applying electrical current into the body while simultaneously making voltage measurements on the body surface. The process of measuring voltages on a patient's torso must be shielded from the current pulses by breaking the voltage measuring connections for a short period of time. This process of temporarily breaking the measuring connections is called blanking. The invention carefully breaks these measuring connections a short time before a current pulse is delivered to the body, and reconnects them to the body a short time after the delivery. The period of time that the voltage measuring capability is disconnected has been designed to be as short as possible without allowing deleterious effects from a current pulse to affect the measuring process. The apparatus is therefore further able to deliver a current pulse to a patient's body with a minimal loss of monitored voltage information.
Another limitation of the prior art is the lack of teachings regarding the well-known problems that are created by the resistance across the chest when electrical current is placed into the body, and especially across the heart. We have therefore developed and designed hardware capable of overcoming these problems that exist when applying low levels of current through the chest to effect discernible changes in the electrical activity of the heart. Specifically, we have applied a modified version of a prior-art precision current regulator, as described in the preferred embodiment, to overcome these limitations.